17alpha-thienyl-and 17alpha-thiazolyl 3-lower alkoxy-1, 3, 5 (10)-estratrien-17beta-ols



United States Patent The present invention relates to 17a-thienyland 17athiazolyl 3-lower alkoxy-1,3,5(l0)-estratrien-17B-ols.

The said 17ot-thienyland 17u-thiazo1y1 3-lower alkoxy- 3,163,642 Patented Dec. 29, 1964 ICC to hormonic substances. For instance, 3-methoxy-17oz- (2-thienyl)-1,3,5(l0)-estratrien-l7fl-ol and 3-methoxy- 17a-(2-thiazoly1)-1,3,5(l0)-estratrien-17/i-o1 show complete inhibition of gonadotrophin secretion in the para- 1,3,5(10)-estratrien l7fi-o1s are represented by the for- V mula I on I l J:---R

wherein R is thienyl or thiazolyl and R is a lower alkyl group (e.g. methyl, ethyl, propyl, butyl).,

It is an object of the present invention to embody the Una-substituted 3-lower alkoxyl-1,3,5(10)-estratrien-l7fiols of Formula I. Another object of the invention is to embody a process for preparing the Not-substituted 3-lower alkoxy-1,3,5(l0)-estratrien-17fl-ols (I). A further object of the invention is to embody the physiologically active 17OL-SllbStitllted 3-lower alkoxy-1,3,5.(l0) 'estratrien-l7fl-ols (I). These and other objects Will be apparent to those conversant with the art to which the present invention pertains from the/subsequent description. i The objective l7wsubstituted 3-1ower a1koxy-1,3,5 (10)-estratrien-17B-ol (I) is prepared from 3-lower alkoxy-1,3,5(10)-estratrien-17-one by subjecting the latter to reaction with an organic metal compound containing the group corresponding to the above designated symbol R, followed by hydrolysis.

The starting 3-lower alkoxy-1,3,5(l0)-estratrien-17-one (estrone 3-lower alkyl ether) is a Well known compound and can be represented by the formula:

dioxane, tetrahydrofuran, benzene, toluene) at a temperature from'O to' 100 C., usually at room temperature (10 to 30 C.). The resulting addition-product is then hydrolyzed in an acidic medium, preferably by treating the same with an aqueous solution of .an -acidic salt (e.g. ammonium chloride, ammonium bromide, I ammonium sulfate). 1

The thus-produced"Un -substituted 3'-1ower alkoxy-l, 3,5(l0)-estratrien 17{3ol (I) is useful as an antagonist ples.

utes and then refluxed for a while.

biotic mice which received subcutaneously a total of 0.1

milligram. Other Not-substituted 3-lower alkoxy-1,3,5.

(10)-estratrienl7B-ols also show similar activities.

Practical and presently-preferred embodiments of the present invention are illustrated in the following exam- In these examples, the abbreviations each have conventional meanings: e.g., mg.=milligram(s), g.= gram(s), ml.=millilitre(s), C.=degrees centigrade, Anal. Calcd.:analysis calculated.

Example 1 f mind To a solution of metallic lithium (384 mg.) in anhydrous ether (70 ml.), there is added bromobenzene (4.30 g.), and the resultant mixture is stirred in nitrogen stream at room temperature (10 to 30 C.) for about 20min- After cooling the resulting phenyl lithium solution at 30 C., a solution of 2-bromothiazole (2.48 g.) in benzene (20 ml.) is dropwise added thereto and allowed to stand at --10 C. for 30 minutes. To the resulting mixture, there is dropwise added a solution of 3-methoxy-1,3,5(10)-estratrien 17-one (1.56 g.) in benzene (50 ml.), and the mixture is stirred at room temperature overnight. The reaction mixture is combined with an aqueous solution of ammonium chloride and shaken With ether. The ether extract a is washed with water, dried and evaporated to dryness.

The residue is chromatographed on alumina (40 g.). The eluates with petroleum ether-benzene (1 1-1 :2) and benzene are crystallized from ether and recrystallized from a mixture of acetone and hexane to give 3-methoxyl7a-(2-thiazolyl)-1,3,5(10)-estratrien-17fl-o1 (1.49 g.) as flat needles melting at 167 to 168? C. [M +646: 2 (chloroform). 1 UVMQBQ? m (e): 245 (6,360); 279 (2,080); 287 (1,910)

IR villi? end- 3374,, 3176, 8116, 1612, 1585, 1504, 1237, 719 a AnaL -Calcd. for CggIIzqOgNSI C, 71.51; H, 7.37; N, 3.79; S, 8.68. Found: C, 71.38; H, 7.42; N, 4.05; S, 8.78. v 7 Example 2 i To a'solution of butyl lithium prepared from metallic lithium (395 mg.) and 'butyl bromide (3.86 g.) in an hydrous ether (70 ml.) innitrogen stream, there is added thiophene (2.37 g.), and the resultant mixture is allowed To the thus-produced to stand at -10 C. for 1 hour. solution'of 2-thienyl lithium, there is added a solution of 3-inethoxy-1,3,5(l0)-estratrien-17-one (1.60 g.) in anhydrous benzene, and the resultant mixture is stirred With ether.

for 4 hours at room temperature and then allowed to stand overnight. The reaction mixture is combined with an aqueous solution of ammonium chloride and shaken The ether extract is Washed successively with an aqueous solution of sodium carbonate and water, dried and evaported to dryness. The residue is crystallized from ether and recrystallized from a mixture of dichloromethane and acetone to give 3-n1ethoXy-17a-(2- thienyl)-1,3,5(10)-estratrien-17fl-ol (1.46 g.) as prisms melting at 190 to 192 C. [M 71.5i2 (chloroform).

UV X2533? m,u.(e): 227 (14,700), 231 (15,100), 279 (2,050), 287.5 (1,850). IR 12? (rm- 3607, 3143, 3093, 3035, 1610, 1586, 1504, 1237, 725

What is claimed is:

1. 3-lower trien- 17 {3-01.

a1koxy-17u-(2-thiaz0ly1) -1,3,5 10)-estra- 2. 3 methoxy 17u-(2-thiazo1yl)-1,3,5(10)-estratrien- 3. 3 -lower a1koXy-17u- (2-thienyl) -1 ,3,5 10 )-estratrien- 4. 3-methoxy-17a- (Z-thienyl) -1,3,5 10 -est1'atrien-17B- References Cited in the file of this patent 

1. 3-LOWER ALKOXY-17A-(2-THIAZLOYL)-1,3,5(10)-ESTRATRIEN-17B-OL.
 3. 3-LOWER ALKOXY-17A-(2-THIENYL)-1,3,5(10)-ESTRATRIEN17B-OL. 